The mixture of the geranyl esters of these two farnesylacetic acid isomers is a useful product possessing anti-ulcerogenic activity, as is reported in Medicina Experimentalis 7, 171 (1962), which is widely used as a pharmaceutical at present. Since trans,trans-geranyl farnesylacetate is the predominant isomer in the trans,trans/cis, trans mixture, it is therefore highly desirable to find a convenient method for the preparation of the pure form of this compound and/or its precursor, i.e. trans,trans-farnesylacetic acid (I).
Farnesylacetic acid and esters thereof may, in theory, occur in four stereoisomeric forms, due to the two double bonds in 4- and 8-position which are capable of forming cis,trans-geometric isomers. Besides the above-mentioned forms (I) and (II), there exist the two other possible isomeric forms, namely trans(4), cis(8)- and cis(4), cis (8)-farnesylacetic acid which correspond to the following formulas:
trans(4), cis(8)-farnesylacetic acid: ##STR4##
cis(4), cis(8)-farnesylacetic acid: ##STR5## However, these two isomeric forms are only of scientific interest and have no economic significance, at present.
All four of the isomeric forms of farnesylacetic acid or their esters are obtained in admixture with each other if one starts, as usual, from a mixture of cis- and transnerodilol (see British Pat. No. 938 712 as well as U.S. Pat. No. 3,928,403).
Of course, the number of possible stereoisomers may be restricted from four to two, if one starts from only one isomer of nerolidol. In fact, the use of a starting nerolidol possessing a previously defined double bond geometry (trans or cis) leads to only one pair of isomers (I and II, or III and IV, respectively). However, since a second double bond is introduced by the subsequent reaction step, it is not possible to obtain pure trans,trans-farnesylacetic acid solely by the choice of a pure nerolidol isomer.
However, processes for production of trans,trans-farnesylacetic acid are already known. These are either based on the principle of stereospecific synthesis (Japanese Patent Application J 5-1029-437 of Teikoku Kagaku Sangyo) or the separation of isomers by fractional distillation (German Offenlegungsschrift No. 2,538,532). A process for the production of the geranyl esters by column-chromatography is also known [see Helv. chim. Acta 53, 1827 (1970)].
Yet all these known processes have serious disadvantages. Thus the process of sterospecific synthesis involves a laborious purification of the starting product, geranylacetone, via the semi-carbazone according to the method of Isler et al. (Helv. chim. Acta 39, 897 (1956). Besides, the process involves the use of expensive intermediate products, is complicated and represents a Wittig reaction, of which it is known (see Quart. Rev. 1964, 9, 255) that it will yield trans or cis isomers, depending upon the conditions applied, but that there remains much to be desired as far as the stereochemical purity of the product obtained is concerned.
The separation of isomers of farnesylacetic acid by fractional distillation in vacuo involves the use of a special equipment and, due to the close proximity of the boiling points of the components, requires critical working conditions.
The column-chromatographical separation of the geranyl esters is only suitable for work on a laboratory scale.